Taking Medicines in Pregnancy: What’s Safe and What’s Not - What The Experts Say

By Ron Batagol

Ever since the Thalidomide tragedy half a century ago, pregnant women have, too often, been given conflicting and often confusing advice from friends or from distorted media reports as to the safety of various chemicals and medicines. Often such medicines may be recommended for treating medical conditions that they have, such as epilepsy, high blood pressure or diabetes.
The author, Ron Batagol, is a pharmacy and obstetric drug information consultant, who, over many years, has researched, lectured and written several Reference Guides on the safety of drug in pregnancy for doctors, pharmacists and other health professionals.
This book is a must-read for pregnant women who want to be informed of any risks that we know of, to the unborn infant, as against the benefits to the mother’s health, of medicines which may be used to treat their various medical conditions. The information, reflecting the expert consensus of what the risk versus benefit is for each medicine, will help pregnant women when seeking the advice of the doctor, about whether or to take the medicine during pregnancy.
Ron sees this book as fulfilling an important educative role, by providing for the first time, information on medication safety directly to pregnant women themselves, in an easily-readable, plain English form, in a way that reflects the consensus of expert obstetric opinion with regard to the safety of various medicines. The book deals separately with the components of all of the commonly-used medicines. It also includes a general discussion of how we assess the safety of medicines used during pregnancy and discusses the safety of herbal and other non-prescription medicines, Ron also discusses the safety issues of exposure to recreational or environmental chemicals during pregnancy, and the dangers of smoking and excessive alcohol use, whilst cautioning against unnecessarily scaring women who may have occasionally or inadvertently had small amounts of alcohol during pregnancy.

• Language: English
• Publisher: ReadOnTime BV
• Release date: Jul 3, 2013
• ISBN: 9781742842257

Ron Batagol

The author, Ron Batagol is a Melbourne-based pharmacist who has worked in all areas of pharmacy practice including clinical, management, and obstetric drug information, and has, over the past 30 years, researched, lectured and written Reference Guides on the safety of drugs in pregnancy for doctors, pharmacists and other health professionals. Ron strongly believes that it is important for women to be able to easily access clearly written and accurate information to enable them to be fully informed of the expert consensus of safety issues, when they discuss their own situation with their doctors, regarding the use of medications in pregnancy. In this book, he has used the descriptive approach, written in plain English, which he believes is the best way to achieve this, which will also overcome the anxiety and confusion which is generated by the current alphabetical pregnancy risk classification system used in Australia and elsewhere.

Book preview

Taking Medicines in Pregnancy – What’s Safe and What’s Not – What The Experts Say

A Plain English Guide

Ron Batagol

Taking Medicines During Pregnancy

What’s Safe and What’s Not

Smashwords Edition

Copyright © 2013 Ron Batagol, PhC, FSHP, ACIS, ACSA Dip. Jnl

Obstetric Drug Information Author, Lecturer and Consultant,

Nunawading, Vic 3131, Australia

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher.

The information, views, opinions and visuals expressed in this publication are solely those of the author(s) and do not reflect those of the publisher. The publisher disclaims any liabilities or responsibilities whatsoever for any damages, libel or liabilities arising directly or indirectly from the contents of this publication.

A copy of this publication can be found in the National Library of Australia.

ISBN:  978–1-742842–25-7 (pbk.)

Published by Book Pal

www.bookpal.com.au

I wish to acknowledge the work of my dear late wife Irene, who acted as research assistant, set up the template and typed and proof-read the original draft manuscript for this book

Acknowledgements

I am grateful to Dr. Christine Tippett, Consultant Obstetrician and Gynaecologist, for her review of the material and advice on its content.

Thanks to Mr. Rodney Whyte, Specialist Obstetric Drug Information Pharmacist, for his review and comments of the content of this book.

Thanks to Dr. Geraldine Moses, Clinical and Drug Information Pharmacist, for her review and helpful comments regarding the introductory and general discussion section of the book.

Disclaimer

This book is written with the purpose of giving pregnant women insight into the consensus of expert opinion regarding the safety in use of medications which may be taken during pregnancy.

It is published as an educational guide only and must not be relied upon as a basis for making clinical decisions by individual pregnant women, who should always consult manufacturer’s information and their own medical and clinical advisors with regard to any proposed course of action relating to the safety of taking specific medicines during pregnancy.

The author relies on medical and scientific opinion expressed in articles and scientific studies and makes no representation, express or implied, with regard to the accuracy of the information contained in this book and does not warrant or hold responsibility or liability for the validity or for any errors or omissions that may be made.

Contents

Introduction

Section 1

General Discussion of Principles and some Specific Issues of Importance on the Safety of Medicines used in Pregnancy

From the world of myths and monsters to thalidomide and beyond

How drugs affect the developing fetus and discussion of specific issues relating to teratogenicity and fetal toxicity

How do medicines cross the placenta and affect the developing infant (fetus)?

Categorising the safety of drugs used during pregnancy Where do drugs and chemicals fit into the overall picture of birth defects and their causes?

What methods are used to assess whether or not a drug is a teratogen?

A short summary of the risk versus benefit considerations of various medicines and chemicals when used during pregnancy

Alcohol

Smoking

Recreational Drugs

Heroin, Cocaine, Amphetamines and Cannabis Vitamin A and Analogues

Stilboestrol (Des) and Other Sex Hormones Antiepileptic (Anticonvulsant) Drugs

Radiographic Procedures

Cytotoxic (Anti-Cancer) Drugs

Lithium

Leflunomide

Ribavirin

Ace Inhibitors (Acis) and Angiotensin Receptor Blockers (Arbs)

Tetracyclines

Metronidazole

Paroxetine

Vaccination During Pregnancy

Non-Prescription Medicines

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Folic Acid Supplementation in Pregnancy

Herbal Products in Pregnancy

Chemicals in Everyday Use

Caution with Certain Foods During Pregnancy

Section 2

Plain English Guide for Pregnant Women on the Safety of Specific Medicines when Used During Pregnancy

The Australian System of Categorising Drug Safety in Pregnancy

Important Note to the Reader A Guide to the Alphabetical Listing of Medicines

Plain English Guide for Pregnant Women on the Safety of Specific Medicines when Used During Pregnancy

Index of Brand Names of Medications with Cross-References to Alphabetical Generic (Chemical) Names

Introduction

Having a baby is one of the most wonderful and exhilarating of life’s experiences, and one of the most moving events that a family shares.

Although central and critical to the survival of the human species, and the most natural of human endeavours, until 40–50 years ago having a baby was fraught with underlying risks of severe life threatening complications or even death, for both mother and infant.

In recent times, with advances in obstetrics worldwide, as well as rapid developments in techniques for caring for and improving survival rates for very ill and premature infants, these risks have been dramatically reduced in developed countries.

Along with the improvement in obstetric outcomes has been the recognition that, as in other areas of medicine, the role of the pregnant woman has changed from being the passive recipient of medical or surgical services to that of an active participant in the decision-making process. Inherent in this role change is the need to provide the pregnant woman with useful and accurate information upon which informed decisions can be made.

Since the thalidomide tragedy of 1961, we have realised that medications which may be taken by the pregnant woman may pass through the placenta into the developing infant (or fetus). During the first three months of pregnancy, when the infant’s basic bodily structures and functions are being developed, these medications may disrupt the normal pattern of development of structures or organs, leading to birth abnormalities.

Medicines that have this effect are called teratogens. This term comes from the Greek word 'teratos', meaning monster, designating the sometimes monstrous appearance that a severe or crippling abnormality may have in an affected infant.

Since the thalidomide tragedy, a small number of chemical teratogens have been identified. With the development of the science of teratology, the study of the causes of birth defects, there have been significant advances in our understanding of the problems. These days, largely because of the thalidomide episode and its ramifications, drugs are systematically and thoroughly tested experimentally for toxic side effects and, in particular, for their potential teratogenic effects on unborn infants.

By contrast, in the late 1950s and early 60s, this was not the case and, although a broad range of testing for overall toxicity was carried out prior to the release of drugs onto the market, there was no dedicated evaluation protocol designed to see if a drug or chemical had an adverse effect on a developing infant when given to pregnant women.

We now also understand that it is not only necessary to examine the effect of a drug during the first trimester (approximately the first three months) of pregnancy to see if it may be a teratogen, but that it is also necessary to take into account other effects that we call pharmacological effects on the fetus or unborn baby, beside teratogenicity, when a medicine may be used especially later in pregnancy. Thus, some of the medicines used for treating various medical conditions that may arise in the mother whilst pregnant, or may be present before pregnancy, pass through the placenta and may have an effect on the fetus quite unrelated to birth abnormalities.

Some examples of such effects are the sedation and effects on muscle tone, nerve impulses, or even blood pressure in newborn infants whose mothers have taken high doses of various sedatives, drugs used for depression and anxiety, or other medicines affecting blood pressure or the nervous system during pregnancy. Similarly, some medicines used to treat rheumatic and arthritic diseases can have adverse effects on the newborn baby if the mother uses these medications in late pregnancy.

On the other hand, some medications, such as those used to treat heart conditions, severe blood pressure, diabetes, or epilepsy, must be continued throughout pregnancy in order to ensure that the mother remains well and that the fetus is able to develop in the most favourable conditions inside the womb. For these medications, it is essential to be able to weigh up the beneficial effects and to measure these against the adverse effects, so that the pregnancy can be monitored and can proceed safely with the mother receiving her essential effective treatment.

Most (97%) of all newborn infants are healthy and free of birth defects. Of the 3% of infants who are born with a birth defect the exact cause cannot be identified in the vast majority of cases, but we know that genetic and other factors play a part. A small number of drugs and chemicals have been identified as contributing to birth defects and other adverse pregnancy outcomes.

In 1989 the Australian Drug Evaluation Committee (ADEC), following the lead of the United States and Scandinavian countries, developed a comprehensive alphabetical categorisation for all medicinal drugs that identified and ranked their relative risks to the unborn infant when used during pregnancy. This ADEC listing has been updated and reviewed on a continuing basis with all drugs given a risk rating as they are released onto the Australian market.

These developments, together with the advances made since the thalidomide tragedy in our understanding of teratology already referred to, mean that we are now in a better position than we have ever been to offer advice to the pregnant woman on the safety of medications used in pregnancy.

My own interest and involvement in this important area of specialised therapeutics is tied up with the fact that, when I joined the pharmacy department at Melbourne’s Royal Women’s Hospital as deputy chief pharmacist in the late 1970s, I set up and ran the hospital’s Obstetric Drug Information Centre, which answered telephone queries on the safety of drugs used in pregnancy and whilst breastfeeding. Queries came from medical, nursing and other health professional staff within the hospital and also from the general community, as well as directly from patients. I developed an interest in researching, and compiling data on the safety of drugs used in pregnancy.

I wrote three editions of a reference guide on drugs and pregnancy in the 1980s and the early 1990s, which was widely used by doctors, pharmacists and other health professionals, as well as medical educators, both in Australia and overseas, for clinical referral, research and teaching. I have also lectured widely to various student and professional groups over many years on this subject.

The information on the safety of various drugs when used during pregnancy, which I reviewed over several years, came into sharp focus as I became acutely aware of the difficulty that obstetricians had in making the decisions that would be of the most benefit to pregnant women and their precious cargo.

Most importantly of all, it became readily apparent to me that pregnant women who may have complex medical conditions, such as hypertension, epilepsy or diabetes requiring medications to ensure the health, growth and survival of themselves and their unborn children, had difficulty obtaining adequate independent, authenticated reassurance that the medications that they required were safe to use during pregnancy. Indeed, much of the advice that they routinely received from their health advisors was overly defensive and cautious with a tendency to recommend avoiding even those drugs that will assist in ensuring the health and safety of both the mother and the developing fetus.

Without such advice they remain, as one authority has called it, therapeutic orphans!

This situation occurred, even though in 1989 Australia had set up a series of alphabetical categories of risk in pregnancy for all marketed drugs to guide doctors and other health professionals in their advice to pregnant women.

As I will describe shortly, much of the overly defensive reaction occurred because of the long-term effects of what I have termed the post-thalidomide knee-jerk reaction, coupled with the standard overly legalistic and defensive disclaimers accompanying product information for almost all marketed drugs, following the thalidomide tragedy.

It is for that reason that I have decided to write a plain English guide which includes the opinion of experts in the field, so as to assist pregnant women in understanding which drugs they consider to be safe to use and which ones need to be used with caution during pregnancy.

This book is written with the aim of assisting the woman who is pregnant with appropriate information regarding the expert obstetric opinion about the safety of specific drugs that she may be taking, or is contemplating taking, so as to ensure that when she discusses her specific medical situation with her doctor, she is fully informed about the risks where they exist for some medications, or, conversely, the margin of safety that may exist for other medications.

Although beyond the use of medicines during pregnancy, I will also very briefly summarise risks where they are present from consumption or exposure to various chemicals in our day-to-day environment.

Hopefully, this will serve to allay unrealistic anxiety and concern that pregnant women often have about everyday chemicals with which they come into contact, whilst alerting them to the potential hazards of others, such as alcohol, tobacco, various other recreational drugs, and certain chemicals in industrial or specific hobby activities, of which they need to be made aware.

It must be emphasised that this book is not written as a substitute for the medical advice and guidance that is critically important and must be specifically tailored by the doctor to meet each individual pregnant woman’s medical situation.

Ron Batagol, PhC, FSHP, ACIS, ACSA, Dip. Jnl

Obstetric Drug Information Author,

Lecturer and Consultant,

Nunawading, Vic 3131, Australia

Section 1

General Discussion of Principles and some Specific Issues of Importance on the Safety of Medicines used in Pregnancy

From the world of myths and monsters to thalidomide and beyond

Throughout the ages society has had a fear of and a morbid fascination with infants born with severe birth abnormalities, as well as an abiding need to find a simple cause or explanation for them.

The journey from the world of myths and monsters to the world of modern teratology was a slow and tortuous one.

In the pre-scientific era, the apparition of babies with monstrous appearances triggered a collective of imaginative tales and fanciful explanations suggesting that the deformed infants were a sign of catastrophic events, or of pregnant women co-habiting with monsters and devils, or even that the abnormalities were caused by maternal exposure to a frightening experience, such as a bad dream during pregnancy.

The dawn of modern teratology (the dedicated scientific study of the causes of birth abnormalities) occurred in Australia in 1941 when an Australian eye specialist, Dr. Norman Gregg, discovered that contracting German measles during pregnancy could result in a variety of birth defects, including eye defects, deafness and other life threatening congenital abnormalities, such as heart disease.

Then in 1962 came the thalidomide tragedy, identified by another Australian doctor, Dr. William McBride (together with Professor W. Lenz of Germany), in which over 8000 infants worldwide were born with severe and often crippling abnormalities including the absence of properly-formed arms and legs. Their mothers had taken the drug thalidomide early in their pregnancies, which was widely believed to be harmless at the time.

There is currently litigation before the Australian courts in which it is asserted that the manufacturer and distributor of thalidomide did not act speedily enough to inform consumers and authorities of the toxic potential of the drug, and that they did not pay appropriate attention to the potential of the drug to cause damage to the embryo if taken in pregnancy.

Interestingly, in the USA, a young medical advisor named Dr. Frances Kelsey, from the FDA, resisted pressures to allow thalidomide to be released in that country and as a result there were very few thalidomide-affected infants in the USA. Nevertheless, the thalidomide tragedy had profound consequences around the world.

From 1961 onwards, regulatory authorities in countries worldwide established very stringent standards of testing that were required before any drug could be marketed.

An unfortunate consequence of the thalidomide tragedy is what I have termed the post-thalidomide knee-jerk reaction, which describes the tendency to indiscriminately label every drug that may be taken during pregnancy as a potential teratogen. This is usually done to deter patients and their medical advisors from using the drug without giving any indication of what the actual risk would be, even if it were essential to the mother’s well-being.

In 1989, following moves in the USA and Sweden, Australia developed an alphabetical system for categorising the risk versus benefits of drugs in pregnancy in order to assist doctors and other health advisors to guide women on the choice of medicines commonly used during pregnancy. (Drugs in Pregnancy: An Australian Categorisation of the Risk of Drug use in Pregnancy. Woden: The Australian Drug Evaluation Committee (ADEC); 1989)

Three further updated booklets were produced, between 1992 and 1999 after periodic review and inclusion of new products by the TGA/ADEC-commissioned Advisory Working Parties, of which I was a member.

It is important to note that compliance by drug manufacturers and sponsors with the TGA alphabetical risk categorisation system is voluntary.

However, I have to say that most manufacturers and sponsors do comply and that the majority of product information and consumer medicines information (CMI) leaflets do contain an accurate representation of the TGA recommendations.

In recent years, especially in the United States, there has been a dedicated move to change from alphabetical pregnancy risk allocation to a narrative description of the most recently updated definitive expert consensus of safety or otherwise for each marketed drug together with, access to links summarising the supporting evidence for the recommendations made for that drug.

To date, Australia’s medicines regulatory agency (TGA) has not reconvened the Advisory Working Party, and, to my knowledge, has not therefore sought expert advice on a plan to enable Australia to move from its alphabetical risk category system to a more easily understood and less confusing narrative method of explaining the risk versus benefits of taking various medicines during pregnancy. Also, without the the ongoing advice of a Working Party, confusion may arise about drug safety in pregnancy for some drugs. For instance, TGA has recently changed Fludrocortisone from category A to C, and does not appear to have liaised with drug manufacturers to change incorrect pregnancy category risk listings for some other cortisone-like drugs, as published in prescription product guides.

References for further reading

Brent. RL, Beckman D, Landel C. Clinical Teratology. Current Opinion in Paediatrics 1993; 5: 201–211.

Warkany J. Congenital Malformations – Notes and Comments. Chicago: Year Book Medical Publishers Inc; 1981.

Brodsky I. Congenital Abnormalities, Teratology and Embryology: Some evidence of Primitive Man’s Knowledge as Expressed in Art and Lore in Oceania. Med J Aust 1943; 1:417.

Stevenson RE, Hall JG, Goodman RM. Human Malformations and Related Anomalies. Vol 1. Oxford: Oxford University Press; 1993.

Ballantyne JW. Antenatal Pathology and Hygiene: The Embryo. Chicago: Chicago Medical Book Co; 1904.

Burgess MA. Gregg’s Rubella Legacy 1941–1991. [Editorial]. Med J Aust 1991; 155: 355–7.

Gregg N. Congenital cataract following German measles in the Mother. Trans Ophthalmology 1941; 3: 35–46.

Henning Sjostrom H, Nillson R, editors. Thalidomide and the Power of the Drug Companies. Middlesex: Penguin Books; 1972.

Nicol B. McBride: Behind the Myth. Crows Nest: Aust. Broadcasting Corp; 1989.

Lenz W. A short history of Thalidomide Embryopathy. Teratology 1988; 38: 203–215.

McBride WG. Thalidomide and Congenital Abnormalties. Lancet 1961; 2: 1358.

Taussig H. A Study of the German outbreak of Phocomelia. JAMA 1962; 180: 1106–1114.

The Insight Team of the Sunday Times, Suffer Little Children: The Story of Thalidomide. London: Deutch A; 1979.

Warkany J. Why I doubted that thalidomide was the cause of the epidemic of limb defects of 1959 to 1961. Teratology 1988; 38: 217–219.

The Federal Food, Drug and Cosmetic Act (FD&C Act) of 1938.

The 1962 Kefauver-Harris Amendment to the Federal Food, Drug and Cosmetic Act (FD&C Act) of 1938.

Commission on Drug Safety, Report. Conference on Prenatal Effects of Drugs. Chicago: 1963.

Goldenthal E.I. Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use. Washington: Food and Drug Administration, Washington; 1966.

How drugs affect the developing fetus and discussion of specific issues relating to teratogenicity and fetal toxicity

How do medicines cross the placenta and affect the developing infant (fetus)?

Medicines taken by the mother may pass across the placental barrier, dissolved in the blood being transferred to the fetus, and thereby enter the fetal circulatory system.

Medicines and other chemicals can only cause birth abnormalities during the period we call organogenesis, which occurs from the 17th day after conception (fertilisation of the egg by the sperm) up until the 70th day after conception. Before the 17th day from conception, the embryo (fertilised egg) will either survive intact or won’t survive at all and this is called the all or none period.

Whether, and to what extent, drugs or other chemicals pass across the placenta depends on a number of physical and chemical factors affecting the passage of substances across biological membranes (which act like sieves).

It is important to realise that large molecules are unable to cross the placenta, simply because the physical size of the molecule is too large to fit through the pores of the membrane, except in the rare event of molecular breakdown.

Examples of molecules that are too large to pass through the placenta are insulin, which is used to treat diabetes, and Heparins (both heparin and its low molecular weight equivalents), which are used to treat and prevent blood clotting. All these substances are composed of a large number of protein-like substances with each molecule thousands of times the weight of hydrogen. Also some of the recently developed drugs used to treat a variety of diseases are of very large molecular weight and therefore cannot pass through the placenta to the fetus. For example, Erythropoietin and Darbepoetin, which are used in renal failure – Infliximab and Etanercept, which are used for rheumatoid arthritis, and the various Interferons and Pegylated Interferons, which are used for a variety of diseases including some forms of cancers and hepatitis. Another drug that is widely used in medicine, as well as in medically supervised cosmetic procedures, is Botulinum Toxin (or Botox). This is also a very large molecule and will not cross the placenta.

Every drug (or medicine) is assigned a pregnancy risk category when marketing approval is given, so that the drug can be used in Australia. The Australian categorisation system was modelled on the Swedish system, which was set up in 1978. The FDA in the United States also set up an alphabetical categorisation system in 1979.

The systems used in Sweden and Australia are similar, with regard to their safest category A definition, whilst the FDA requires an unrealistically high quality of data, e.g. the availability of controlled studies in pregnant women that fail to demonstrate a risk to the fetus are needed for a drug to be assigned to category A.

Therefore, many drugs on the US market, which would be category A in Australia or Sweden, are assigned to category C in the FDA System, (which says risk cannot be ruled out).

By contrast, in Australia and Sweden, category C is reserved for drugs that may have an adverse pharmacological effect on the infant but do not cause abnormalities.

Also, in the Swedish and Australian